Gyamfi Obed A, Bortey-Sam Nesta, Donkor Abigail B, White Carl W, Logue Brian A
Department of Chemistry and Biochemistry, South Dakota State University, Box 2202, Brookings, SD, 57007, USA.
Pediatrics-Pulmonary Medicine, University of Colorado-Denver, Denver, CO, 80045, USA.
J Pharm Anal. 2020 Apr;10(2):157-163. doi: 10.1016/j.jpha.2019.12.005. Epub 2019 Dec 13.
The noxious effects from exposure to toxic inhalation hazards (TIHs, such as isocyanates, chlorine, etc.) are known to be triggered by the activation of transient receptor potential ankyrin 1 (TRPA1) ion channel. Antagonists of TRPA1 have shown near complete attenuation of the noxious effects from TIH exposure. One of the TRPA1 antagonists, (1,3)-1-(4-fluorophenyl)-2-methyl-1-pentene-3-one oxime (A-967079), has shown impressive efficacy, high selectivity, high potency, and oral bioavailability. Although a validated method to quantify A-967079 in biological matrices is vital for the further development of A-967079 as a therapeutic agent, no method for its analysis from any matrix is currently available. Hence, a rapid and simple HPLC-MS/MS method was developed and validated to quantify A-967079 in rabbit plasma. The method presented here features an excellent LOD of 25 nM and a wide linear range (0.05-200 μM), with good accuracy and precision (100 ± 10.5% and <14.2% relative standard deviation, respectively). The stability of A-967079 in plasma was excellent for most of the storage conditions evaluated. The method was successfully applied to determine A-967079 from treated animals and it may facilitate the development of this TRPA1 antagonist as a therapeutic agent against the noxious effects of TIH exposure.
已知暴露于有毒吸入危害物（如异氰酸酯、氯等）产生的有害影响是由瞬时受体电位锚蛋白1（TRPA1）离子通道的激活引发的。TRPA1拮抗剂已显示出几乎完全减轻了暴露于有毒吸入危害物产生的有害影响。TRPA1拮抗剂之一，(1,3)-1-(4-氟苯基)-2-甲基-1-戊烯-3-酮肟（A-967079），已显示出令人印象深刻的疗效、高选择性、高效力和口服生物利用度。尽管一种经过验证的在生物基质中定量A-967079的方法对于将A-967079开发为治疗剂至关重要，但目前尚无从任何基质中分析它的方法。因此，开发并验证了一种快速简便的HPLC-MS/MS方法来定量兔血浆中的A-967079。本文介绍的方法具有出色的25 nM检测限和宽线性范围（0.05 - 200 μM），具有良好的准确度和精密度（分别为100 ± 10.5%和<14.2%相对标准偏差）。在评估的大多数储存条件下，A-967079在血浆中的稳定性极佳。该方法已成功应用于测定经处理动物体内的A-967079，它可能有助于将这种TRPA1拮抗剂开发为一种治疗剂，以对抗暴露于有毒吸入危害物产生的有害影响。
